Treatment with the noncovalent BTK inhibitor pirtobrutinib (Jaypirca) led to an objective response rate (ORR) of 81.6% (95% CI, 76.5%-85.9%) in patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) previously treated with a covalent BTK inhibitor, according to findings from the final analysis of the phase 1/2 BRUIN trial (NCT03740529) that were presented at the 2025 ASH Annual Meeting.1
Best responses included complete response (CR; n = 11; 3.9%), CR with incomplete blood count recovery (n = 1; 0.4%), non–partial response (PR; n = 3; 1.1%), PR (n = 189; 67.0%), and PR with lymphocytosis (n = 26; 9.2%). In subgroup analysis, the highest ORRs were seen in patients with deletion 11q (n = 47; ORR, 91.5%; 95% CI, 79.6%-97.6%), complex karyotype (n = 33; ORR, 90.9%; 95% CI, 75.7%-98.1%), and 17p deletion and/or TP53 mutation (n = 104; ORR, 87.5%; 95% CI, 79.6%-93.2%). The populations that appeared to derive the least benefit were patients with mutated PLCg2 (n = 18; ORR, 55.6%; 95% CI, 30.8%-78.5%), unmutated BTK C481 (n = 97; ORR, 74.2%; 95% CI, 64.3%-82.6%), and mutated IGHV (n = 32; ORR, 75.0%; 95% CI, 56.6%-88.5%).
“Pirtobrutinib continues to show favorable efficacy and promising overall survival [OS],” William G. Wierda, MD, PhD, lead study author and Endowed Distinguished Professor Jane and John Justin Distinguished Chair in Leukemia Research in the Department of Leukemia, Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center in Houston, and coauthors wrote in the poster.
What Stands Out From the Final BRUIN Dataset
- Pirtobrutinib achieved an ORR of 81.6% in patients previously treated with covalent BTK inhibitors, with promising durability and survival outcomes.
- The agent remained well tolerated, showing low rates of treatment-related discontinuation and fewer high-grade toxicities than typically seen with covalent BTK inhibitors.
- Efficacy was consistent across subgroups, although responses were lower in patients with PLCg2 mutations, unmutated BTK C481, and mutated IGHV.
What challenges drive the need for a non-covalent BTK inhibitor like pirtobrutinib?
Intolerance or treatment resistance remains an issue with covalent BTK inhibitors despite their valued integration into the CLL/SLL armamentarium. Pirtobrutinib is a selective, noncovalent BTK inhibitor that was designed to work against common mechanisms associated with resistance to covalent inhibitors.
Earlier findings from the BRUIN trial illustrated the agent’s efficacy and safety in patients with relapsed/refractory disease, including those with prior exposure to covalent inhibition. Data from the trial led to the agent’s accelerated approval from the FDA in December 2023, which was converted to full approval on December 3, 2025.2,3
The phase 1 dose-escalation and -expansion portion of the trial modeled a 3+3 design, which allowed for intra-patient dose escalation, cohort expansion at doses deemed safe, and treatment with 25 to 300 mg of once daily pirtobrutinib via 28-day cycles.1 In phase 2, patients received 200 mg of once-daily pirtobrutinib.
A total of 778 patients were enrolled: 166 with mantle cell lymphoma, 317 with CLL/SLL, and 295 with other malignancies. Of the 317 patients with CLL/SLL, 35 were BTK naive, and 282 had been exposed to covalent BTK inhibition. Of the latter group, 154 patients were BCL2 naive, and 128 had received BCL2 inhibition.
Eligible patients were at least 18 years old and had previously treated, active disease in need of therapy, and an ECOG performance status between 0 and 2.
Key end points included safety/tolerability, determination of the maximum tolerated dose/recommended phase 2 dose, pharmacokinetics, ORR, progression-free survival (PFS), time to next treatment (TTNT), and OS.
Baseline characteristics across the board of patients with prior exposure to covalent BTK inhibition, BCL2 inhibition, and those naive to BCL2 inhibition revealed that most were male; had received prior BTK inhibition, anti-CD20 therapy, and chemotherapy; had discontinued treatment because of progressive disease; and had unmutated IGHV.
How effective is pirtobrutinib after prior covalent BTK inhibition?
The median duration of response (DOR) was 18.4 months (95% CI, 14.8-20.3), and the 36-month DOR rate was 28.0% (95% CI, 21.6%-34.7%). At median follow-up of 49.9 months the median TTNT was 23.2 months (95% CI, 20.3-29.4). The 12-, 24-, 36-, 48-, and 60-month TTNT rates were 74.7%, 49.9%, 34.1%, 23.3%, and 21.5%, respectively.
Median PFS was 18.7 months (95% CI, 16.6-21.8) at median follow-up of 44.2 months. The 12-, 24-, 36-, 48-, and 60-month PFS rates were 67.1%, 38.1%, 25.0%, 21.6%, and 17.6%, respectively. PFS was also subdivided between patients who were BCL2 naive and exposed. The median PFS was 15.9 months (95% CI, 13.6-17.5) in the exposed population and 22.3 months (95% CI, 19.3-27.6) in the naive population. The 12-, 24-, 36-, 48-, and 60-month PFS rates in the exposed cohort were 60.8%, 25.0%, 14.0%, 14.0%, and 14.0%, respectively. The 12-, 24-, 36-, 48-, and 60-month PFS rates in the naive cohort were 72.1%, 47.9%, 32.9%, 27.7%, and 21.7%, respectively.
In all patients who received covalent BTK inhibition, the median OS was not estimable (95% CI, 47.8 months-NE) at a median follow-up of 46.5 months. The 12-, 24-, 36-, 48-, and 60-month OS rates were 85.5%, 72.2%, 62.0%, 56.0%, and 54.2%, respectively.
What does the safety profile reveal about pirtobrutinib’s tolerability?
The median time on treatment was 20.0 months (IQR, 9.6-37.7). TRAEs leading to dose reduction and discontinuation occurred in 11 (3.9%) and 9 (3.2%) patients, respectively.
All-cause adverse effects (AEs) that occurred in at least 20% of patients included fatigue (any grade, 38.7%; grade ≥3, 1.8%), neutropenia (35.8%; 29.8%), diarrhea (30.5%; 0.4%), cough (29.8%; 0%), contusion (27.7%; 0%), COVID-19 (28.4%; 6.0%), dyspnea (23.4%; 2.5%), nausea (23.4%; 0%), and abdominal pain (21.6%; 2.1%). AEs of interest included infections (76.2%; 36.5%), bruising (31.2%; 0%), rash (25.2%; 1.1%), arthralgia (23.0%; 1.4%), hemorrhage (25.2%; 3.2%), hypertension (16.0%; 5.3%), and atrial fibrillation/flutter (5.0%; 2.1%).
Treatment-related adverse effects (TRAEs) that occurred in at least 20% of patients included fatigue (any grade, 3.9%; grade ≥3, 0%), neutropenia (20.6%; 16.3%), diarrhea (8.9%; 0%), cough (2.1%; 0%), contusion (18.8%; 0%), COVID-19 (0.7%; 0%), dyspnea (0.7%; 0.4%), nausea (3.9%; 0%), and abdominal pain (2.1%; 0.4%). AEs of interest included infections (14.9%; 5.7%), bruising (20.2%; 0%), rash (5.7%; 0.4%), arthralgia (4.6%; 0%), hemorrhage (8.2%; 1.4%), hypertension (3.9%; 0.7%), and atrial fibrillation/flutter (1.4%; 0.7%).
“Pirtobrutinib remains well tolerated with low rates of dose reduction or discontinuation due to TRAEs and low rates of grade 3 or greater hypertension, hemorrhage/hematoma, and atrial fibrillation/atrial flutter, which are risks with covalent BTK inhibitor treatment,” the authors concluded.
Disclosures: No disclosures were listed.
References
- Wierda W, Brown J, Ghia P, et al. Pirtobrutinib in post-BTKi CLL/SLL: final update from the phase 1/2 BRUIN study with more than 5-years follow-up. Blood. 2025;146(suppl 1):2115. doi:10.1182/blood-2025-2115
- FDA grants accelerated approval to pirtobrutinib for chronic lymphocytic leukemia and small lymphocytic lymphoma. FDA. Updated December 7, 2023. Accessed December 7, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-pirtobrutinib-chronic-lymphocytic-leukemia-and-small-lymphocytic
- FDA grants traditional approval to pirtobrutinib for chronic lymphocytic leukemia and small lymphocytic lymphoma. FDA. December 3, 2025. Accessed December 7, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-traditional-approval-pirtobrutinib-chronic-lymphocytic-leukemia-and-small-lymphocytic
